Metformin, Sulfonylureas, or Other Antidiabetes Drugs and the Risk of Lactic Acidosis or Hypoglycemia

OBJECTIVE: Lactic acidosis has been associated with use of metformin. Hypoglycemia is a major concern using sulfonylureas. The aim of this study was to compare the risk of lactic acidosis and hypoglycemia among patients with type 2 diabetes using oral antidiabetes drugs. RESEARCH DESIGN AND METHODS: This study is a nested case-control analysis using the U.K.-based General Practice Research Database to identify patients with type 2 diabetes who used oral antidiabetes drugs. Within the study population, all incident cases of lactic acidosis and hypoglycemia were identified, and hypoglycemia case subjects were matched to up to four control patients based on age, sex, practice, and calendar time. RESULTS: Among the study population of 50,048 type 2 diabetic subjects, six cases of lactic acidosis during current use of oral antidiabetes drugs were identified, yielding a crude incidence rate of 3.3 cases per 100,000 person-years among metformin users and 4.8 cases per 100,000 person-years among users of sulfonylureas. Relevant comorbidities known as risk factors for lactic acidosis could be identified in all case subjects. A total of 2,025 case subjects with hypoglycemia and 7,278 matched control subjects were identified. Use of sulfonylureas was associated with a materially elevated risk of hypoglycemia. The adjusted odds ratio for current use of sulfonylureas was 2.79 (95% CI 2.23–3.50) compared with current metformin use. CONCLUSIONS: Lactic acidosis during current use of oral antidiabetes drugs was very rare and was associated with concurrent comorbidity. Hypoglycemic episodes were substantially more common among sulfonylurea users than among users of metformin.Merck SA, Lyon, Franc

Examples of mathematical modeling tales from the crypt

Mathematical modeling is being increasingly recognized within the biomedical sciences as an important tool that can aid the understanding of biological systems. The heavily regulated cell renewal cycle in the colonic crypt provides a good example of how modeling can be used to find out key features of the system kinetics, and help to explain both the breakdown of homeostasis and the initiation of tumorigenesis. We use the cell population model by Johnston et al. (2007) Proc. Natl. Acad. Sci. USA 104, 4008-4013, to illustrate the power of mathematical modeling by considering two key questions about the cell population dynamics in the colonic crypt. We ask: how can a model describe both homeostasis and unregulated growth in tumorigenesis; and to which parameters in the system is the model most sensitive? In order to address these questions, we discuss what type of modeling approach is most appropriate in the crypt. We use the model to argue why tumorigenesis is observed to occur in stages with long lag phases between periods of rapid growth, and we identify the key parameters

On the proportion of cancer stem cells in a tumour

It is now generally accepted that cancers contain a sub-population, the cancer stem cells (CSCs), which initiate and drive a tumour’s growth. At least until recently it has been widely assumed that only a small proportion of the cells in a tumour are CSCs. Here we use a mathematical model, supported by experimental evidence, to show that such an assumption is unwarranted. We show that CSCs may comprise any possible proportion of the tumour, and that the higher the proportion the more aggressive the tumour is likely to be

Evolutionary history and identification of conservation units in the giant otter, Pteronura brasiliensis.

The giant otter, Pteronura brasiliensis, occupies a range including the major drainage basins of South America, yet the degree of structure that exists within and among populations inhabiting these drainages is unknown. We sequenced portions of the mitochondrial DNA (mtDNA) cytochrome b (612 bp) and control region (383 bp) genes in order to determine patterns of genetic variation within the species. We found high levels of mtDNA haplotype diversity (h = 0.93 overall) and support for subdivision into four distinct groups of populations, representing important centers of genetic diversity and useful units for prioritizing conservation within the giant otter. We tested these results against the predictions of three hypotheses of Amazonian diversification (Pleistocene Refugia, Paleogeography, and Hydrogeology). While the phylogeographic pattern conformed to the predictions of the Refugia Hypothesis, molecular dating using a relaxed clock revealed the phylogroups diverged from one another between 1.69 and 0.84 Ma, ruling out the influence of Late Pleistocene glacial refugia. However, the role of Plio-Pleistocene climate change could not be rejected. While the molecular dating also makes the influence of geological arches according to the Paleogeography Hypothesis extremely unlikely, the recent Pliocene formation of the Fitzcarrald Arch and its effect of subsequently altering drainage pattern could not be rejected. The data presented here support the interactions of both climatic and hydrological changes resulting from geological activity in the Plio-Pleistocene, in shaping the phylogeographic structure of the giant otter

SPARC-Dependent Cardiomyopathy in Drosophila

Background—The Drosophila heart is an important model for studying the genetics underpinning mammalian cardiac function. The system comprises contractile cardiomyocytes, adjacent to which are pairs of highly endocytic pericardial nephrocytes that modulate cardiac function by uncharacterized mechanisms. Identifying these mechanisms and the molecules involved is important because they may be relevant to human cardiac physiology. Methods and Results—This work aimed to identify circulating cardiomodulatory factors of potential relevance to humans using the Drosophila nephrocyte-cardiomyocyte system. A Kruppel-Like Factor 15 (dKlf15) loss-of-function strategy was used to ablate nephrocytes and then heart function and the hemolymph proteome were analysed. Ablation of nephrocytes led to a severe cardiomyopathy characterized by a lengthening of diastolic interval. Rendering adult nephrocytes dysfunctional by disrupting their endocytic function or temporally-conditional knock-down of dKlf15 led to a similar cardiomyopathy. Proteomics revealed that nephrocytes regulate the circulating levels of many secreted proteins, the most notable of which was the evolutionarily conserved matricellular protein SPARC (Secreted Protein Acidic and Rich in Cysteine), a protein involved in mammalian cardiac function. Finally, reducing SPARC gene dosage ameliorated the cardiomyopathy that developed in the absence of nephrocytes. Conclusions—The data implicate SPARC in the non-cell autonomous control of cardiac function in Drosophila and suggest that modulation of SPARC gene expression may ameliorate cardiac dysfunction in humans

Relativistic Mean Field Approximation in a Density Dependent Parametrization Model at Finite Temperature

In this work we calculate the equation of state of nuclear matter for different proton fractions at zero and finite temperature within the Thomas Fermi approach considering three different parameter sets: the well-known NL3 and TM1 and a density dependent parametrization proposed by Typel and Wolter. The main differences are outlined and the consequences of imposing beta-stability in these models are discussed.Comment: 13 pages, 10 figure

The role of quark mass in cold and dense pQCD and quark stars

For almost twenty years the effects of a nonzero strange quark mass on the equation of state of cold and dense QCD were considered to be negligible, thereby yielding only minor corrections to the mass-radius diagram of compact stars. By computing the thermodynamic potential to first order in \alpha_s, and including the effects of the renormalization group running of the coupling and strange quark mass, we show that corrections can be of the order of 25%, and dramatically affect the structure of compact stars.Comment: 4 pages, 2 figures, contribution to QM2005 proceeding

Neurogene Stammzelltransplantation in die Kochlea

Zusammenfassung: Hintergrund: Die Stammzelltherapie ist insbesondere im Hinblick auf eine Applikation im Innenohr interessant, da die Haarzellen nicht regenerieren. Einmal abgestorbene Haarzellen werden nicht ersetzt, es kommt zu einem irreversiblen Hörverlust. In den vergangenen Jahren konnten Stammzellen mit wechselndem Erfolg ins Innenohr appliziert werden, zum Teil haben sie sich zu Innenohrzellen entwickelt. In der vorliegenden Studie wollten wir untersuchen, wie sich neuronale Vorläuferzellen verhalten, wenn sie in vitro und in vivo auf ein geschädigtes Innenohr aufgebracht werden. Methoden: Neuronale Vorläuferzellen wurden von E9,5Tage alten Mausembryonen isoliert und danach mit einem Virus, der das grün fluoreszierende Protein (GFP) exprimiert, infiziert. In der Folge wurden die GFP+-neuralen Vorläuferzellen sowohl auf ein geschädigtes Corti-Organ in vitro aufgebracht als auch Mäusen ins zuvor geschädigte Innenohr in vivo appliziert. Anschließend wurden die Vorläuferzellen bzw. ihr Bezug zum Corti-Organ analysiert. Ergebnisse: Sowohl auf ein geschädigtes Corti-Organ aufgebrachte GFP+-neurale Vorläuferzellen als auch in vivo in geschädigte Innenohren transplantierte GFP+-neurale Vorläuferzellen konnten nach Transplantation nachgewiesen werden. Interessanterweise haben sich die GFP+-neuralen Vorläuferzellen nicht zufällig auf dem Organ niedergelassen, sondern ein gewisses Muster gezeigt. Insbesondere konnte nach der In-vivo-Applikation gesehen werden, dass die GFP+-neuralen Vorläuferzellen sich im Bereich des Corti-Organs in der Region von abgestorbenen Haarzellen angesiedelt haben. Schlussfolgerung: Neuronale Vorläuferzellen haben ein großes Potenzial, einmal abgestorbene Haarzellen zu ersetzen. Allerdings braucht es noch intensive Forschung bis zur klinischen Anwendun

The association between thyroid disorders and incident gout: population-based case-control study

Thyroid hormones influence kidney function and thereby might alter serum urate levels, a major risk factor for gouty arthritis.; To assess the risk of developing incident gout in association with hypothyroidism or hyperthyroidism.; Retrospective population-based case-control analysis.; UK-based Clinical Practice Research Datalink, a primary care research database.; We identified adult patients with a diagnosis of incident gout between 1990 and 2014. We matched one control to each gout case in terms of age, sex, general practice, calendar time, and years of active history in the database.; We used conditional logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for developing gout in association with hypo- or hyperthyroidism and adjusted for potential confounders.; The study population encompassed 68,159 incident gout cases, of whom 78.8% were male, and the same number of matched controls. There was no increased risk of gout in patients with hypothyroidism: adjusted OR of gout of 1.12 (95% CI 1.05-1.20) compared with no hypothyroidism. Current short-term treatment of thyroid hormone replacement therapy was associated with an adjusted OR of gout of 1.54 (95% CI 1.24-1.92), compared with no treatment. Neither hyperthyroidism nor current treatment with thyroid suppression therapy was associated with gout (adjusted OR, 1.08 [95% CI 0.95-1.22] and 0.82 [95% CI 0.57-1.17], respectively).; This large observational study does not provide evidence that hypothyroidism or hyperthyroidism, irrespective of treatment, is associated with a clinically relevant increased risk of developing incident gout. There may be an exception among patients with newly diagnosed and treated hypothyroidism

Modelling multiscale aspects of colorectal cancer

Colorectal cancer (CRC) is responsible for nearly half a million deaths annually world-wide [11]. We present a series of mathematical models describing the dynamics of the intestinal epithelium and the kinetics of the molecular pathway most commonly mutated in CRC, the Wnt signalling network. We also discuss how we are coupling such models to build a multiscale model of normal and aberrant guts. This will enable us to combine disparate experimental and clinical data, to investigate interactions between phenomena taking place at different levels of organisation and, eventually, to test the efficacy of new drugs on the system as a whole